Amino acid amides of phenoxybutyric acid derivatives

ABSTRACT

A compound of the formula: 
     
       
         
         
             
             
         
       
     
     where X is phenyl substituted at the 3, 4 and 5 positions with R1, R2 or R3 which are selected from hydrogen, chloro, lower alkyl of 1 to 5 carbons, phenoxy, phenyl, naphthyl, or phenyl (lower) alkyl where the lower alkyl group has 1-5 carbon atoms and m is 0 or 1; Y is —CONH— or —NHCONH— where the nitrogen atoms are unsubstituted or substituted with other phenoxyisobutyric acid derivatives, or the residue of a phenoxyisobutyric acid and n is 0 or 1; Z is unsubstituted phenyl when m is 1 and n is 1; when Y is 0, X is 0; Z is also substituted.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of provisional application Ser. No.61/464,679, filed Mar. 8, 2011

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STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISK

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REFERENCE TO A MICROFICHE APPENDIX

Not Applicable

BACKGROUND OF THE INVENTION

1) Field of the Invention

This invention is directed to novel compounds which are useful inpharmaceutical compositions for human and veterinary use and in cosmeticcompositions as well as in anti-aging compositions.

2) Description of Related Art

It is known in the art that elevated concentration of reducing sugars inthe blood and in the intracellular environment results in thenonenzymatic formation of glycation and dehydration condensationcomplexes known as advanced glycation end-products or aminaglycation endproducts (AGEs). Nonenzymatic glycation is a complex series of reactionsbetween reducing sugars and amino groups of proteins, lipids, and DNA.These complex products form on free amino groups on proteins, on lipidsand on DNA (Bucala and Cerami, 1992; Bucala et al., 1993; Bucala et al.,1984). This phenomenon is called “browning” or a “Maillard” reaction andwas discovered early in the last century by the food industry (Maillard,1916). The reaction is initiated with the reversible formation ofSchiffs base which undergoes rearrangement to form a stable Amadoriproduct. Both Schiffs base and Amadori product further undergo a seriesof reactions through dicarbonyl intermediates to form AGEs. Thesignificance of a similar process in biology became evident only afterthe discovery of the glycosylated hemoglobins and their increasedpresence in diabetic patients (Rahbar, 1968; Rahbar et al., 1969). Inhuman diabetic patients and in animal models of diabetes, thesenonenzymatic reactions are accelerated and cause increased AGE formationand increased glycation of long-lived proteins such as collagen,fibronectin, tubulin, lens crystallin, myelin, laminin and actin, inaddition to hemoglobin and albumin, and also of LDL associated lipidsand apoprotein. Moreover, brown pigments with spectral and fluorescentproperties similar to those of late-stage Maillard products have alsobeen found in vivo in association with several long-lived proteins suchas crystalline lens proteins and collagen from aged individuals. Anage-related linear increase in pigments was observed in human duracollagen between the ages of 20 to 90 years. AGE modified proteinsincrease slowly with aging and are thought to contribute to normaltissue remodeling. Their level increases markedly in diabetic patientsas a result of sustained high blood sugar levels and lead to tissuedamage through a variety of mechanisms including alteration of tissueprotein structure and function, stimulation of cellular responsesthrough AGE specific receptors or the generation of reactive oxygenspecies (ROS) (for a review see Boel et al., 1995). The structural andfunctional integrity of the affected molecules, which often have majorroles in cellular functions, become disturbed by these modifications,with severe consequences on affected organs such as kidney, eye, nerve,and micro-vascular functions (Silbiger et al., 1993; Brownlee et al.,1985).

Structural changes on macromolecules by AGEs are known to accumulateunder normal circumstances with increasing age. This accumulation isseverely accelerated by diabetes and is strongly associated withhyperglycemia. For example, formation of AGE on protein in thesubendothelial basement membrane causes extensive cross-link formationwhich leads to severe structural and functional changes inprotein/protein and protein/cell interaction in the vascular wall(Haitoglou et al., 1992; Airaksinen et al., 1993).

Enhanced formation and accumulation of advanced glycation end products(AGEs) have been implicated as a major pathogenesis process leading todiabetic complications, normal aging, atherosclerosis and Alzheimer'sdisease. This process is accelerated by diabetes and has been postulatedto contribute to the development of a range of diabetic complicationsincluding nephropathy (Nicholls and Mandel, 1989), retinopathy (Hammeset al., 1991) and neuropathy (Cameron et al., 1992). Particularly,tissue damage to the kidney by AGEs leads to progressive decline inrenal function, end-stage renal disease (ESRD) (Makita et al., 1994),and accumulation of low-molecular-weight (LMW) AGE peptides(glycotoxins) (Koschinsky et al., 1997) in the serum of patients withESRD (Makita et al., 1991). These low molecular weight (LMW)-AGEs canreadily form new crosslinks with plasma or tissue components, e.g., lowdensity lipoprotein (LDL) (Bucala et al., 1994) or collagen (Miyata etal., 1993) and accelerate the progression of tissue damage and morbidityin diabetics.

Direct evidence indicating the contribution of AGEs in the progressionof diabetic complications in different lesions of the kidneys, the ratlens and in atherosclerosis has been reported (Vlassara et al., 1994;Vlassara et al., 1995; Horie et al., 1997; Matsumoto et al., 1997;Soulis-Liparota et al., 1991; Bucala and Vlassara, 1997; Bucala andRahbar, 1998; Park et al., 1998). Indeed, the infusion of pre-formedAGEs into healthy rats induces glomerular hypertrophy and mesangialsclerosis, gene expression of matrix proteins and production of growthfactors (Brownlee et al., 1991; Vlassara et al., 1995). Several lines ofevidence indicate that the increase in reactive carbonyl intermediates(methylglyoxal, glycolaldehyde, glyoxal, 3-deoxyglucosone,malondialdehyde and hydroxynonenal) is the consequence of hyperglycemiain diabetes. “Carbonyl stress” leads to increased modification ofproteins and lipids, followed by oxidant stress and tissue damage(Baynes and Thorpe, 1999; Onorato et al., 1998; McLellan et al., 1994).Further studies have revealed that aminoguanidine (AG), an inhibitor ofAGE formation, ameliorates tissue impairment of glomeruli and reducesalbuminuria in induced diabetic rats (Soulis-Liparota et al., 1991;Itakura et al., 1991). In humans, decreased levels of hemoglobin(Hb)-AGE (Makita et al., 1992) concomitant with amelioration of kidneyfunction as the result of aminoguanidine therapy in diabetic patients,provides more evidence for the importance of AGEs in the pathogenesis ofdiabetic complications (Bucala and Vlassara, 1997).

The global prevalence of diabetes mellitus, in particular in the UnitedStates, afflicting millions of individuals with significant increases ofmorbidity and mortality, together with the great financial burden forthe treatment of diabetic complications in this country, are majorincentives to search for and develop drugs with a potential forpreventing or treating complications of the disease. So far themechanisms of hyperglycemia-induced tissue damage in diabetes are notwell understood. However, four pathogenic mechanisms have been proposed,including increased polyol pathway activity, activation of specificprotein kinase C (PKC) isoforms, formation and accumulation of advancedglycation endproducts, and increased generation of reactive oxygenspecies (ROS) (Kennedy and Lyons, 1997). Most recent immunohistochemicalstudies on different tissues from kidneys obtained from ESRD patients(Hone et al., 1997) and diabetic rat lenses (Matsumoto et al., 1997), byusing specific antibodies against carboxymethyllysine (CML),pentosidine, the two known glycoxidation products and pyrraline, havelocalized these AGE components in different lesions of the kidneys andthe rat lens, and have provided more evidence in favor of protein-AGEformation in close association with generation of ROS to be majorfactors in causing permanent and irreversible modification of tissueproteins. Therefore, inhibitors of AGE formation and antioxidants holdpromise as effective means of prevention and treatment of diabeticcomplications.

The Diabetic Control and Complications Trial (DCCT), has identifiedhyperglycemia as the main risk factor for the development of diabeticcomplications (The Diabetes Control and Complications Trial ResearchGroup, 1993). Compelling evidence identifies the formation of advancedglycation endproducts as the major pathogenic link between hyperglycemiaand the long-term complications of diabetes (Makita et al., 1994;Koschinsky et al., 1997; Makita et al., 1993; Bucala et al., 1994;Bailey et al., 1998).

The reactions between reducing sugars and amino groups of proteins,lipids and DNA undergo a series of reactions through dicarbonylintermediates to generate advanced glycation endproducts (Bucala andCerami, 1992; Bucala et al., 1993; Bucala et al., 1984).

In human diabetic patients and in animal models of diabetes, AGEformation and accumulation of long-lived structural proteins andlipoproteins have been reported. Many reports indicate that glycationinactivates metabolic enzymes (Yan and Harding, 1999; Kato et al., 2000;Verbeke et al., 2000; O'Harte et al., 2000). The glycation-inducedchange of immunoglobin G is of particular interest. Reports of glycationof the Fab fragment of IgG in diabetic patients suggest that immunedeficiency observed in these patients may be explained by thisphenomenon (Lapolla et al., 2000). Furthermore, an association betweenIgM response to IgG damaged by glycation and disease activity inrheumatoid arthritis has been reported (Lucey et al., 2000). Also,impairment of high-density lipoprotein function by glycation has beendescribed (Hedrick et al., 2000).

Methylglyoxal (MG) has recently received considerable attention as acommon mediator and the most reactive dicarbonyl to form AGEs (Phillipsand Thomalley, 1993; Beisswenger et al., 1998). It is also a source ofreactive oxygen species (ROS) (free radicals) generation in the courseof glycation reactions (Yim et al., 1995).

Nature has devised several humoral and cellular defense mechanisms toprotect tissues from the deleterious effects of “carbonyl stress” andaccumulation of AGEs, e.g., the glyoxylase systems (I and II) and aldosereductase catalyze the detoxification of MG to D-lactate (McLellan etal., 1994). Amadoriases are also a novel class of enzymes found inAspergillus which catalyze the deglycation of Amadori products(Takahashi et al., 1997). Furthermore, several AGE-receptors have beencharacterized on the surface membranes of monocytes and on macrophage,endothelial, mesangial and hepatic cells. One of these receptors, RAGE,a member of the immunoglobulin superfamily, has been found to have awide tissue distribution (Schmidt et al., 1994; Yan et al., 1997). Thediscovery of various natural defense mechanisms against glycation andAGE formation suggests an important role of AGEs in the pathogenesis ofvascular and peripheral nerve damage in diabetes. MG binds to andirreversibly modifies arginine and lysine residues in proteins. MGmodified proteins have been shown to be ligands for the AGE receptor(Westwood et al., 1997) indicating that MG modified proteins areanalogous (Schalkwijk et al., 1998) to those found in AGEs. Furthermore,glycolaldehyde, a reactive intermediate in AGE formation, generates anactive ligand for macrophage scavenger receptor (Nagai et al., 2000).The effects of MG on LDL have been characterized in vivo and in vitro(Bucala et al., 1993).

Lipid peroxidation of polyunsaturated fatty acids (PUFA), such asarachidonate, also yields carbonyl compounds; some are identical tothose formed from carbohydrates (Al-Abed et al., 1996), such as MG andGO, and others are characteristic of lipids, such as malondialdehyde(MDA) and 4-hydroxynonenal (HNE) (Requena et al., 1997). The latter twocarbonyl compounds produce lipoxidation products (Al-Abed et al., 1996;Requena et al., 1997). A recent report emphasizes the importance oflipid-derived MDA in the cross-linking of modified collagen and indiabetes mellitus (Slatter et al., 2000). A number of AGE compounds,both fluorophores and nonfluorescent, are involved in crosslinkingproteins and have been characterized (Baynes and Thorpe, 1999). Inaddition to glucose derived AGE-protein crosslinks, AGE crosslinkingalso occurs between tissue proteins and AGE-containing peptide fragmentsformed from AGE-protein digestion and turnover. These reactiveAGE-peptides, now called glycotoxins, are normally cleared by thekidneys. In diabetic patients, these glycotoxins react with the serumproteins and are a source for widespread tissue damage (He et al.,1999).

However, detailed information on the chemical nature of the crosslinkstructures remain unknown. The crosslinking structures characterized todate, on the basis of chemical and spectroscopic analyses, constituteonly a small fraction of the AGE crosslinks which occur in vivo, withthe major crosslinking structure(s) still unknown. Most recently, anovel acid-labile AGE-structure, N-omega-carboxymethylarginine (CMA),has been identified by enzymatic hydrolysis of collagen. Itsconcentration was found to be 100 times greater than the concentrationof pentosidine (Iijima et al., 2000) and it is assumed to be a major AGEcrosslinking structure.

In addition to aging and diabetes, the formation of AGEs has been linkedwith several other pathological conditions. IgM anti-IgG-AGE appears tobe associated with clinical measurements of rheumatoid arthritisactivity (Lucey et al., 2000). A correlation between AGEs and rheumatoidarthritis was also made in North American Indians (Newkirk et al.,1998). AGEs are present in brain plaques in Alzheimer's disease and thepresence of AGEs may help promote the development of Alzheimer's disease(Durany et al., 1999; Munch et al., 1998; Munch et al., 1997). Uremicpatients have elevated levels of serum AGEs compared to age-matchedcontrols (Odani et al., 1999; Dawnay and Millar, 1998). AGEs have alsobeen correlated with neurotoxicity (Kikuchi et al., 1999). AGE proteinshave been associated with atherosclerosis in mice (Sano et al., 1999)and with atherosclerosis in persons undergoing hemodialysis (Takayama etal., 1998). A study in which aminoguanidine was fed to rabbits showedthat increasing amounts of aminoguanidine led to reduced plaqueformation in the aorta thus suggesting that advanced glycation mayparticipate in atherogenesis and raising the possibility that inhibitorsof advanced glycation may retard the process (Panagiotopoulos et al.,1998). Significant deposition of N(epsilon)-carboxymethyl lysine (CML),an advanced glycation endproduct, is seen in astrocytic hyalineinclusions in persons with familial amyotrophic lateral sclerosis but isnot seen in normal control samples (Kato et al., 1999; Shibata et al.,1999). Cigarette smoking has also been linked to increased accumulationof AGEs on plasma low density lipoprotein, structural proteins in thevascular wall, and the lens proteins of the eye, with some of theseeffects possibly leading to pathogenesis of atherosclerosis and otherdiseases associated with tobacco usage (Nicholl and Bucala, 1998).Finally, a study in which aminoguanidine was fed to rats showed that thetreatment protected against progressive cardiovascular and renal decline(Li et al., 1996). The mechanism of the inhibitory effects ofaminoguanidine in the cascade of glycosylation events has beeninvestigated. To date, the exact mechanism of AG-mediated inhibition ofAGE formation is not completely known. Several lines of in vitroexperiments resulted in contrasting conclusions. Briefly, elevatedconcentrations of reducing sugars cause reactions between carbohydratecarbonyl and protein amino groups leading to: 1. Reversible formation ofSchiffs bases followed by 2. Amadori condensation/dehydration productssuch as 3-deoxyglucason (3-DG), a highly reactive dicarbonyl compound(Kato et al., 1990). 3. Irreversible and highly reactive advancedglycosylation endproducts. Examples of early Amadori products areketoamines which undergo further condensation reactions to form lateAGEs. A number of AGE products have been purified and characterizedrecently, each one constituting only minor fractions of the in vivogenerated AGEs. Examples are pyrraline, pentosidine,carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), crossline,pyrrolopyridinium, methylglyoxal lysine dimer (MOLD), Arg-Lys imidazole,arginine pyridinium, cypentodine, piperidinedinone enol and alkyl,formyl, diglycosyl-pyrrole (Vlassara, 1994).

Analysis of glycation products formed in vitro on a synthetic peptidehas demonstrated that aminoguanidine does not inhibit formation of earlyAmadori products (Edelstein and Brownlee, 1992). Similar conclusionswere reached by analysis of glycation products formed on BSA (Requena etal., 1993). In both experiments AGE formation was strongly inhibited byAG as analyzed by fluorescence measurements and by mass spectralanalysis. The mass spectral analysis did not detect peptide complexeswith molecular mass corresponding to an incorporation of AG in thecomplex. Detailed mechanistic studies using NMR, mass spectroscopy andX-ray diffraction have shown that aminoguanidine reacts with AGEprecursor 3-DG to form 3-amino-5- and 3-amino-6-substituted triazines(Hirsch et al., 992). In contrast, other experiments using labeled.sup.14C-AG with lens proteins suggest that AG becomes bound to theproteins and also reacts with the active aldose form of free sugars(Harding, 1990).

Several other potential drug candidates as AGE inhibitors have beenreported. These studies evaluated the agent's ability to inhibit AGEformation and AGE-protein crosslinking compared to that ofaminoguanidine (AG) through in vitro and in vivo evaluations (Nakamuraet al., 1997; Kochakian et al., 1996). It is known thatN-phenacylthiazolium bromide (PTB), which selectively cleavesAGE-derived protein cross-links in vitro and in vivo (Vasan et al.,1996; Ulrich and Zhang, 1997). The pharmacological ability to breakirreversible AGE-mediated protein crosslinking offers potentialtherapeutic use.

It is well documented that early pharmaceutical intervention against thelong-term consequences of hyperglycemia-induced crosslinking prevent thedevelopment of severe late complications of diabetes. The development ofnontoxic and highly effective drugs that completely stopglucose-mediated crosslinking in the tissues and body fluids is a highlydesirable goal. The prototype of the pharmaceutical compoundsinvestigated both in vitro and in vivo to intervene with the formationof AGEs on proteins is aminoguanidine (AG), a small hydrazine-likecompound (Brownlee et al., 1986). However, a number of other compoundswere found to have such an inhibitory effect on AGE formation. Examplesare D-lysine. (Sensi et al., 1993), desferrioxamine (Takagi et al.,1995), D-penicillamine (McPherson et al., 1988), thiamine pyrophosphateand pyridoxamine (Booth et al., 1997) which have no structuralsimilarities to aminoguanidine.

A number of hydrazine-like and non-hydrazine compounds have beeninvestigated. So far AG has been found to be the most useful inhibitorof glycation. AG is also a well known selective inhibitor of nitricoxide (NO) and can also have antioxidant effects (Tilton et al., 1993).

A number of other potential drug candidates to be used as AGE inhibitorshave been discovered recently and evaluated both in vitro and in vivo(Nakamura et al., 1997; Soulis et al., 1997). While the success instudies with aminoguanidine and similar compounds is promising, the needto develop additional inhibitors of AGEs continues to exist in order tobroaden the availability and the scope of this activity and therapeuticutility.

Amino acid compounds through their amino group can be bound to thecarboxylic acid group of phenoxyisobutyric acid to form amidederivatives. These novel amides have increased activity as compared tothe phenoxyisobutyric acid derivative from which they are derived. Onereason for the increased activity is believed to be due to be that theamide derivatives have less affinity to serum albumin than the parentphenoxyisobutyric acid compounds and as a result have higherbioavailability. It is believed that the amides will also be morereadily metabolized in the body.

The compounds of the invention may be synthesized by using generalpeptide synthesis methods including mixed anhydride and active esters.All amino acids including α, β, γ, ε etc. may be used to prepare theamides of the invention. The amino acids may be linear, cyclic orheterocyclic carboxylic acids. Alkali metal salts of the amides that aresynthesized under aqueous conditions are water soluble and are preferredfor administration of the compounds to a patient.

The present inventors have previously reported new classes of compoundswhich are aryl (and heterocyclic) ureido and aryl (and heterocyclic)carboxamido phenoxyisobutyric acids and also benzoic acid derivativesand related compounds as inhibitors of glycation and AGE formation(Rahbar et al., 1999; Rahbar et al., 2000; Rahbar et al., 2002). Seealso U.S. Pat. Nos. 5,093,367; 6,072,072; 6,337,350; 6,605,642 and7,030,133 from which the structures of these patents are incorporatedherein by reference as well as the methods of preparing the compoundsdisclosed in those patents. An elevated concentration of reducing sugars(i.e., glucose) in the blood and in the intracellular environment of ananimal, namely a human, typically results in the nonenzymatic formationof glycation and dehydration condensation complexes known as advancedglycation end-products (AGE). These AGE complex products form on freeamino groups, on proteins, on lipids and on DNA (Bucala and Cerami, AdvPharmacol 23:1-34, 1992; Bucala et al., Proc Natl Acad Sci 90:6434-6438,1993; Bucala et al Proc Natl. Acad Sci 81:105-109, 1984). Thisphenomenon is called “browning” or a “Maillard” reaction and wasdiscovered early in the last century by the food industry (Maillard, AnnChim 5:258-317, 1916). The significance of a similar process in biologybecame evident only after the discovery of the glycosylated hemoglobinsand their increased presence in diabetic patients (Rahbar, Clin ChimActa 20:381-5, 1968; Rahbar et al., Biochem Biophys Res Commun36:838-43, 1969). A diabetic patient's AGE level increases markedly as aresult of sustained high blood sugar levels and often leads to tissuedamage through a variety of mechanisms including alteration of tissueprotein structure and function, stimulation of cellular responsesthrough AGE specific receptors and/or the generation of reactive oxygenspecies (ROS) (for a recent review see Boel et al., J DiabetesComplications 9:104-29, 1995). These AGE have been shown to causecomplications in patients suffering from various pathologicalconditions, including, but not limited to, diabetes mellitus, rheumatoidarthritis, Alzheimer's Disease, uremia and in atherosclerosis in personsundergoing hemodialysis.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula I, as well aspharmaceutical and compositions thereof for cosmetic and antiaging useand methods of using said compounds:

where X is phenyl substituted at the 3, 4 and 5 positions with R1, R2 orR3 which are selected from hydrogen, chloro, lower alkyl of 1 to 5carbons, phenoxy, phenyl, naphthyl, or phenyl (lower) alkyl where thelower alkyl group has 1-5 carbon atoms and m is 0 or 1; Y is —CONH— or—NHCONH— where the nitrogen atoms are unsubstituted or substituted withother phenoxyisobutyric acid derivatives, or the residue of aphenoxyisobutyric acid and n is 0 or 1; Z is unsubstituted phenyl when mis 1 and n is 1; when Y is 0, X is 0; Z is phenyl substituted at the 3,4 and 5 positions with R1, R2 or R3 which are selected from hydrogen,chloro, lower alkyl of 1 to 5 carbons, phenoxy, phenyl, naphthyl, orphenyl (lower) alkyl where the lower alkyl group has 1-5 carbon atoms;and R4 is hydrogen alkyl of 1-5 carbon atoms; aminoalkyl COORS, wherethe alkyl group may be substituted with a carboxyl or histidinesubstituted lower alkyl group having 1-5 carbons and, or is a cycloalkylgroup; R5 is hydrogen or lower alkyl of 1-5 carbons or an acyl-loweralkyl group where the lower alkyl group has 1-5 carbons

Examples of suitable amino acid containing compounds include amino acidcompounds such as valine, 4-aminoisobutyric acid, leucine, 3-aminoisobutyric acid, isoleucine, asparagine, methionine, phenylalanine,proline, tryptophan, glutamic acid, cysteine, glutamine, arginine,histidine, lysine, aspartic acid, glycione, serine, threonine, tyrosine,ε-aminocaproic acid, 1-aminocyclohexanecarboxylic acid, cystine,arginine and the like. Other amino acids include taurine and allunnatural synthetic amino acids.

The compounds of formula 1 may be used topically or systemically. Thetopical uses include anti-aging effects that are achieved by mixing thecompounds with a cosmetic base that is applied to the skin using anamount that forms a thin film. The systemic uses include reduction ofserum cholesterol, anti-glycation in diabetes, treatment ofatherosclerosis, neuro-degenerative diseases, anti-aging of the skin bythe modification of collagen; and prevention of skin wrinkles.

DETAILED DESCRIPTION OF THE INVENTION

The phenoxyisobutyric amides of the invention may be made by reacting amixed anhydride of the phenoxyisobutyric acid derivative in aconventional peptide synthesis using a non-aqueous solvent such astetrahydrofuran with equimolar quantities of triethyl amine and ethylchloroformate using an ice bath with stirring. The reaction product isadded to a solution of one mole of an amino acid (or 0.5 mole of adiamino acid such as cysteine or lysine dissolved in a 2 molar aqueoussolution of NaOH (cooled to ice bath temperature). After 0.5 hours ofstirring at room temperature, the mixture is warmed to 60° C. whilestirring. At this time the tetrahydrofuran is evaporated and the residueis diluted with water and acidified with an acid such as 0.1N HCl or0.1N citric acid. The solution is cooled to crystallize the product.

Alternatively, 4-aminophenoxybutyric acid may be converted to its methylester using an ice cold salt solution (temperature of 0° C.) of Normalthionyl chloride in methanol. The methyl ester hydrochloride salt may bereacted with any appropriate aryl isocyanate to obtain the methyl esterof aryliminocarbonyl phenoxyisobutyric acid methyl ester. Using a hot(temperature ˜50° C.) Normal NaOH solution, the methyl group of theester group is removed. The free acid reacts with the methyl ester ofany amino acid in ethyl acetate solution in the presence ofdicylcohexylcarbodiimide to yield the methyl ester of the of the aminoacid derivative. The methyl ester may be removed by boiling NaOHfollowed by acidification.

An additional procedure for preparing compounds according to theinvention is the formation of active esters. The most successful esteris N-hydroxy succinimide of clofibric acid derivatives which areprepared using the dried acid dissolved in tetrahydrofuran or dioxanewith equimolar quantities of N-hydroxy succinimide and one mole ofdicyclohexylcarbodiimide at room temperature with stirring overnight.After the addition of a small quantity of water to decompose thedicyclohexylcarbodiimide, the reaction mixture is filtered andeventually extracted with ethyl acetate to free the product from anydicyclohexylurea and obtain the pure product in high yields.

The product prepared by this method is identical to the product preparedby using the mixed anhydride method or by the use of esters of aminoacids as described above.

A further method of preparing the amino acid amides of the invention isby dissolving the methyl or ethyl esters of the amino acid in ethyl;acetate and reacting the dissolved ester with the appropriatephenoxybutyric acid derivative in the presence ofdicyclohexylcarbodiimide. After the reaction is complete, thedicyclohexyldicarbodiimide is decomposed by the addition of a smallquantity of water. The solvent is removed by evaporation and the freeamide is precipitated by the addition of an appropriate acid.

The compounds of the present invention inhibit the nonenzymaticformation of glycation and dehydration condensation complexes known asadvanced glycation end-products (AGE). In one embodiment of the presentinvention, a method is provided for administering a medication thatinhibits the nonenzymatic formation of glycation and dehydrationcondensation complexes known as advanced glycation end-products (AGE) toa subject in need thereof, comprising providing at least one medicationthat inhibits the nonenzymatic formation of AGE complexes; andadministering the medication to an patient wherein the nonenzymaticformation of AGE complexes is inhibited.

In another embodiment of the method, the administering step comprises aroute of administration selected from the group consisting of oral,sublingual, intravenous, intracardiac, intraspinal, intraosseous,intraarticular, intrasynovial, intracutaneous, subcutaneous,intramuscular, epicutaneous, transdermal, conjunctival, intraocular,intranasal, aural, intrarespiratory, rectal, vaginal and urethral. Inanother embodiment, the administering step comprises providing themedication on an implantable medical device.

While these medications are typically parameter specific medications,they are efficacious in wound healing, in scar reduction and in thetreatment of burns including damage caused by laser cosmetic therapy.For example, a compound that inhibits the formation of AGE complexes maybe directly applied to in a conventional hydrophilic or oleophilicointment base, or incorporated within, a medical device (i.e., a wounddressing, patch, etc.) and applied to a patient's skin to aid the wouldhealing process.

Any method of administering the medication(s) discussed herein iscontemplated. While it is understood by one skilled in the art that themethod of administration may depend on patient specific factors, themethods of administration include, but are not limited to, generallyparenteral and non-parenteral administration. More specifically, theroutes of administration include, but are not limited to oral,sublingual, intravenous, intracardiac, intraspinal, intraosseous,intraarticular, intrasynovial, intracutaneous, subcutaneous,intramuscular, epicutaneous, transdermal, conjunctival, intraocular,intranasal, aural, intrarespiratory, rectal, vaginal, urethral, etc.Typically, an oral route of administration is preferred.

Of course, it is understood that the medication will be administered inthe appropriate pharmaceutical dosage, depending on the route ofadministration. For example, an oral dosage form may be administered inat least one of the following pharmaceutical dosage forms: tablet;capsule; solution; syrup; elixir; suspension; magma; gel; and/or powder.A sublingual preparation may be administered in at least one of thefollowing pharmaceutical dosage forms: tablet; troche; and/or lozenge. Aparenteral dosage form may be administered in at least one of thefollowing pharmaceutical dosage forms: solution and/or suspension. Anepicutaneous/transdermal dosage form may be administered in at least oneof the following pharmaceutical dosage forms: ointment; cream; infusionpump; paste; plaster; powder; aerosol; lotion; transdermalpatch/disc/solution. A conjunctival dosage form may be administered inat least one of the following pharmaceutical dosage forms: contact lensinsert and/or ointment. An intraocular/intraaural dosage form may beadministered in at least one of the following pharmaceutical dosageforms: solution and/or suspension. An intranasal dosage form may beadministered in at least one of the following pharmaceutical dosageforms: solution; spray; inhalant and/or ointment. An intrarespiratorydosage form may be administered in at least one of the followingpharmaceutical dosage forms: aerosol and/or powder. A rectal dosage formmay be administered in at least one of the following pharmaceuticaldosage forms: solution; ointment and/or suppository. A vaginal dosageform may be administered in at least one of the following pharmaceuticaldosage forms: solution; ointment; emulsion foam; tablet;insert/suppository/sponge. A urethral dosage form may be administered inat least one of the following pharmaceutical dosage forms: solutionand/or suppository.

The above-noted dosage form(s) may include at least one medicationdisclosed herein, either alone or in combination with at least one othermedication disclosed herein or with a medication not disclosed hereinand/or in combination with at least one inert pharmaceutical excipient.These medications may have any release profile including, but notlimited to, an immediate

release, a controlled release and/or a delayed release profile.

The medical devices include, but are not limited to, implantable medicaldevices such as, but not limited to, stents (both vascular andurethral), deposition implants (implantable medication releasingdevice), and/or a medication delivery pumps. Also, contemplated hereinare topically applied medical devices including, but not limited to,patches, gauze, wraps, appliques, dressings, coverings, etc. In the caseof a medical device, at least one medication may be releasably appliedeither to at least a portion of the surface of the device, or to amaterial applied to the surface of a device. Alternatively, at least onemedication may be absorbed and/or adsorbed into or onto the devicematerial so long as the medication may be released from the material ata later time.

The medication may be releaseably applied to the medical device via anyindustrially acceptable method, including, but not limited to, spraycoating, a waterfall method, heat annealing, etc., however, spraycoating is typically preferred. Alternatively, the medical device mayinclude at least one medication, wherein the medication is absorbedand/or adsorbed into or onto the medical device. This may be done by anyindustrially acceptable method. Also, it is contemplated herein that amedical device may include both at least one medication releasablyapplied to the medical device itself and/or a coating applied to thedevice and at least one medication absorbed and/or adsorbed into or ontothe medical device itself.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

In the course of screening different classes of organic compounds forinvestigation of their possible inhibitory and/or breaking effects onadvanced glycation endproducts (AGEs), it has been found that most ofthe phenylureido substituted phenoxy propionic acid derivatives testedhave inhibitory effects and several of these compounds were potentinhibitors of AGE-formation at concentrations much lower than an equallyinhibiting concentration of aminoguanidine.

The mechanism by which this class of compounds inhibits glycation and/orbreaking of glycation, AGE-formation, and crosslinking is yet to beknown in full. Three major mechanisms include anti-inflammatory (PPARRAGE), transient-metal-chelation such as copper and iron, andfree-radical scavenging or trapping of reactive carbonyl intermediateshave been proposed to be responsible for AGE-inhibitory function ofknown AGE-inhibitors.

The mechanism of the inhibitory activities of guanidino compoundinhibitors such as two known inhibitors of glycation (aminoguanidine andmetformin) is that they are postulated to trap MG and otheralpha.-dicarbonyl intermediates of glycation. A most recent study hasdocumented the reaction of metformin with MG and glyoxal (GO), formingguanidino-dicarbonyl adducts further supporting this idea(Ruggiero-Lopez et al., 1999).

Using known assay methods specific for the early (Amadori) and late(post-Amadori) stages of glycation has revealed that some inhibitorshave greater effects in the early stages and some in the late stages ofglycation. However, most of the inhibitor compounds we have investigatedare multistage inhibitors. The reaction of reducing sugars with .alpha.-and .epsilon.-amino groups of proteins is not a random process butrather a site specific reaction which depends on the nature and thevicinity of these chemical groups. The future task is to specificallydefine the site and/or sites of interaction of an inhibitor compound inthe complex series of reactions and intermediate substrates, leading toAGE formation and cross-linking.

The development of the novel inhibitors of glycation, AGE formation, andAGE-protein crosslinking expands the existing arsenals of inhibitors ofglycation reaction that can find therapeutic applications for theprevention of diabetic complications, as well as the prevention of otherdiseases associated with increased glycation of proteins or lipids.Furthermore, the availability of these compounds may prove useful astools to study the cascade of reactions and intermediate substrate inthe process of AGE-formation and AGE-protein cross-linking.

The compounds of the invention and their useful compositions utilized inthe present invention contain agents capable of reacting with the highlyactive carbonyl intermediate of an early glycation product therebypreventing those early products from later forming the advancedglycation end products or in the alternative as agents for “breaking” orreversing the AGE complexes after they form protein crosslinkedcompounds which cause protein aging. Doses of 1-1000 mg per day may beused to inhibit the formation of AGE complexes or to break AGE complexesdepending on the desired effect and the observed response in a patient.The formation of AGE has been linked to several pathologies which may betreated according to the invention including chronic inflammation suchas dry eyes, neuropathy, atherosclerosis, retinopathy, Alzheimer'sdisease, erectile dysfunction and diabetes. The compounds of theinvention are useful for the treatment of pre-diabetes, Type I and TypeII diabetes as well as the prevention and/or treatment of diabeticcomplications such as elevated cholesterol, retinopathy, kidney damage,circulatory disorders, neuropathy and the like. The compounds of theinvention also have activity against rheumatoid arthritis, Alzheimer'sdisease, Wilson's disease, atherosclerosis, neurodegenerative diseases,such as multiple sclerosis, neurotoxins and metabolic syndrome. An oraldose for these conditions is preferred but other routes ofadministration may be utilized. An effective amount of an oral dose willbe from 1-1000 mg daily preferable given in divided doses. It ispresently contemplated that a dose of 250-500 mg daily would bepreferred.

Other utilities envisioned for the present invention are prevention ofaging of the skin by exerting an anti-aging effect that reduces wrinklesand makes the skin smoother. The compounds also inhibit spoilage ofproteins in foodstuffs such as the browning reaction seen in certainfruits. The present agents are also useful in the area of oral hygieneas they prevent discoloration of teeth and may be used as solutions ordispersions in water or a cream at a concentration of 0.1 to 10% byweight. and used as a cosmetic on the skin to improve the smoothness,texture, appearance and to prevent or treat aging of the skin. Aparticular use is the application of compounds to skin for the purposeof increasing the collagen content which will inhibit or reverseenvironmental aging effects. The compounds of the invention reduce theamount of MMP9 in the skin which makes the compounds useful fortraumatic and surgical wounds. They may be used systemically ortopically for scleroderma, acne, psoriasis, inflammation, antioxidanteffects or for chelation of metals. For topical use, the compounds maybe added to hydrophilic or oleophilic cosmetic bases in amounts of 0.01to 10% by weight, and preferably 1-5% or they may be applied as asolution, dispersion or gel. The cosmetic bases include any commerciallyavailable cosmetic cream that is designed for application to the skin.For systemic use, the compounds may be administered orally at a dose of1-1000 mg daily in divided doses. The dose will be adjusted depending onthe observed effects using conventional dosing techniques. The compoundsof the invention have PPAR activity which is an acronym for peroxisomeproliferator activated receptor which are a group of receptor isoformswhich exist across biology. They are intimately connected to cellularmetabolism (carbohydrate, lipid and protein) and cell differentiation.They are also transcript factors. Several types of PPARs have beenidentified: alpha, gamma 1, 2 and 3 as well as delta or beta. The alphaform is expressed in liver, kidney, heart, adipose tissues as well as inother tissues. The gamma 1 form is expressed in virtually all tissuesincluding heart, muscle, colon, kidney, pancreas and spleen tissues. Thegamma 2 form is expressed mainly in adipose tissue (30 amino acids orlonger while gamma 3 is expressed in macrophage, large intestine andwhite adipose tissue. Delta is expressed in many tissues but mainly inbrain, adipose tissue and skin. PPARs dimerize with the retinoidreceptor and bind to specific regions on the DNA of the largest genesand when PPAR binds to its ligand, transcription of target genes isincreased or decreased depending on the gene. The PPAR activity of thecompounds of the invention is a property that confirms that thecompounds of the invention are useful as antidiabetic compounds in themanner that the PPAR active compound pioglitazone is useful whenadministered orally to diabetics. The dose may be from 1 to 1000 mgorally and preferably 250-500 mg orally, daily basis given in divideddoses.

To aid in the administration, the compound may be combined with apharmaceutical acceptable diluent or carrier to form a pharmaceuticaldosage form. The dosage form can be a liquid, solid, gel for immediaterelease or controlled release. Common pharmaceutical diluents orcarriers are described in the Handbook of Pharmaceutical Excipients,4^(th) addition, the United States Pharmacopeia, and Remington'sPharmaceutical Science. The compounds of the invention may be preparedusing one of the following methods: mixed anhydride method (A); activeester method (B) or the amino acid ester method (C).

The reaction scheme for Method (A) is as follows:

where R1, R2, R3 and R4 are as above described.

The reaction scheme for Method (B) is as follows:

where R1, R2, R3 and R4 are as above described; R5 is alkyl of 1-10carbon atoms or phenyl or naphthyl.

The reaction scheme for Method (C) is as follows:

where R1, R2, R3, R4 and R5 are as above described and R6 is an alkyl of1-10 carbon atoms, phenyl, naphthyl, alkylphenyl, phenylalkyl oralkylphenylalkyl where the alkyl group is from 1-10 carbon atoms.

Example 1

To a stirring mixture of 1 mole of clofibric acid (2.145 g) in 25 ml oftetrahydrofuran and 1.4 ml of triethyl amine on an ice-salt bath isslowly added 1 ml of ethyl chloroformate and a solution of 1.3 g (0.01mole) of 4-aminobutyric acid in 7.5 ml of 2N aqueous sodium hydroxidewith 15 ml of tetrahydrofuran. After one hour of stirring at roomtemperature, most of the tetrahydrofuran evaporated. The aqueoussolution was filtered over Celite and acidified with citric acid. Aftertwo hours in a refrigerator, the solid was filtered and air dried giving2.7 g of product (approximately 90% yield) mp 95-97° C. The white powdermay be crystallized from aqueous isopropanol without changing themelting point.

This compound has the following formula:

Example 2

One mole of the following compound:

is dissolved in 8 ml of tetrahydrofuran, 0.15 ml of triethyl amine and0.1 ml (approximately 0.1 mmole) of ethylchloroformate is added to andcooled on an ice salt bath for 0.5 hours. A solution of 3-aminobutyricacid in 1.2 ml of aqueous 1 N NaOH is added to the previously preparedsolution and an off white precipitate is formed. After the addition of15 ml of water and acidification with citric acid, the precipitate wasfiltered, washed with water and dried giving 456 mg (97% yield) of awhite product mp 96-98° C. having the following formula:

Example 3

To a cold solution of 382 mg of a compound of the formula:

in 8 ml of tetrahydrofuran is added 0.15 ml (approximately 1 mmole) oftriethylamine and 0.1 ml (approximately 1 mmole) of ethylchloroformateand the mixture is stirred for 0.5 hours and a solution of 107 mg (1.1mmole) of glycine in 2 ml of aqueous 1 N NaOH with 3 ml of water isadded and stirred for 0.5 hours at room temperature prior to adding 20ml of water. The tetrahydrofuran is evaporated, the mixture is cooledand acidified with citric acid. A off white precipitate forms which iswashed with water and dried to give 400 mg (yield 90%) mp 101-103° C. ofa product of the formula:

Example 4

2.5 mmoles of a compound of the formula:

is added in 15 ml of tetrahydrofuran containing 0.25 ml oftriethylamine, 483 mg of the methyl ester of 1-aminocyclohexane-1-carboxylic acid hydrochloride and 0.515 g (2.5 mmole) ofdicyclohexylcarbodiimide. The resulting mixture is stirred at roomtemperature for an additional 6 hours. The mixture is then suctionfiltered and the solid precipitate is washed with 8 ml oftetrahydrofuran. Evaporation of the tetrahydrofuran gives a lightcolored oil that is dissolved in carbon tetrachloride. The NMR showsthat some unreacted material is present The oil is dissolved in 15 ml ofisopropanol and 5 ml of aqueous 2N NaOH solution, warmed to and stirredfor 1 hour. The resulting mixture is acidified with 0.1N hydrochloricacid and cooled to 0° C. to give 700 mg (54.3% yield) of a producthaving the formula:

Example 5

To a cold solution (0° C.) of 383 mg (1 mmole)3,5-dichlorophenylureidophenoxyisobutyric acid in 8 ml oftetrahydrofuran, 0.15 ml of triethylamine and 0.1 ml ofethylchloroformate are added. After 0.5 hours of stirring, a solution of177 mg (1.1 mmole) of the γ-methyl ester of glutamic acid in 1 ml ofaqueous 1N NaOH solution with 5 ml of water and 5 ml of tetrahydrofuranis added with stirring for 1 hour at room temperature. Thetetrahydrofuran was evaporated until a gum is obtained. The gum wasacidified with 0.1N hydrochloric acid and extracted with ethyl acetate.The resulting product is then dissolved in 2N sodium carbonate solution,filtered, acidified with 0.1 N HCl, cooled in a refrigerator to give 316mg of a crystalline compound (mp 97-99° (approximate yield 60%) havingthe formula:

Example 6

4-chlorobenzoyl chloride (1 mole) is added drop wise to a pyridinesolution of 4-aminophenoxyisobutyric acid (1 mole) while being cooled ona water bath at 0° C. After the mixture is stirred for 1 hour, thepyridine is decomposed with) 1N HCl and a white crystalline product isobtained in the theoretical yield with a mp of 179-180° C. The productis of the following formula:

651 mg (2 mmoles) of a compound of Formula (IX) in 10 ml oftetrahydrofuran is combined with 0.2 ml of ethylchloroformate and 0.3 mlof triethyl amine with stirring on an ice salt bath for one hour. Tothat mixture, is added a cold (0° C.) solution of 240 mg (1 mmole) ofcystine in 2 ml of aqueous 1N NaOH with 3 ml of water in 3 ml oftetrahydrofuran followed by an additional 3 ml of aqueous NaOH at roomtemperature. The resulting mixture is stirred for one hour and the clearsolution acidified with 0.1N HCL and refrigerated for 24 hours prior tofiltering off 820 mg (approximate yield 94%) of the compound of formula(X) mp (softening) 115-117° C. and melting at 125°. The product isrecrystallized by dissolving the compound in chloroform, cooling themixture to 0° C. followed by the addition of excess petroleum etherwhich crystallizes as a white powder without a change in the meltingpoint.

Example 7

To a solution of 2.145 g (0.01 mole) of clofibric acid in 20 ml oftetrahydrofuran, cooled on an ice salt bath, is added 1.4 ml of triethylamine and 1 ml of ethylchloroformate. After stirring the mixture for 0.5hours, a solution of 1.312 g (0.1 mole) of ε-amino caproic acid in 9 mlof 1N aqueous NaOH is added and stirred for one hour at roomtemperature. Most of the tetrahydrofuran is evaporated and the mixtureis acidified with 0.1N HCl to give an oil which is extracted with ethylacetate. After evaporation of the ethyl acetate 3.235 g approximateyield 98.5%) of a colorless oil of formula (XI). The structure offormula (XI) is confirmed with NMR spectroscopy in carbon tetrachloride.Thin layer chromatography on silica gel showed a single spot.

Example 8

To a solution of 3.85 g (0.01 mole) of 4,5-dichlorophenylureidophenoxyisobutyric acid in 3.0 ml of tetrahydrofuran cooled on an icesalt bath while stirring, is added, dropwise, 1.5 ml ofethylchloroformate to form a mixed anhydride solution and a solution ofL-histidine (1.2 g in 0.5 g of LiOH and 10 ml of water) is added all atonce to the mixed anhydride solution with evolution of carbon dioxide.The mixture is stirred overnight and the next day is warmed to atemperature of 50° C. and 30 ml of water is added while an air flow isused to remove the tetrahydrofuran. Atr this time is added sufficientHCl to yield a gum to obtain a white residue of formula (XII) mp (soft)175°; decomposition mp 214° C. with an approximate theoretical yield.The NMR was consistent with the structure ofL-4(3,5-dichlorophenoxyureidophenoxy)isobutyryl histidine hydrochloride.

1. A compound of the formula:

where X is phenyl substituted at the 3, 4 and 5 positions with R1, R2 orR3 which are selected from hydrogen, chloro, lower alkyl of 1 to 5carbons, phenoxy, phenyl, naphthyl, or phenyl (lower) alkyl where thelower alkyl group has 1-5 carbon atoms and m is 0 or 1; Y is —CONH— or—NHCONH— where the nitrogen atoms are unsubstituted or substituted withother phenoxyisobutyric acid derivatives, or the residue of aphenoxyisobutyric acid and n is 0 or 1; Z is unsubstituted phenyl when mis 1 and n is 1; when Y is 0, X is 0; Z is phenyl substituted at the 3,4 and 5 positions with R1, R2 or R3 which are selected from hydrogen,chloro, lower alkyl of 1 to 5 carbons, phenoxy, phenyl, naphthyl, orphenyl (lower) alkyl where the lower alkyl group has 1-5 carbon atoms;and R4 is hydrogen; alkyl of 1-5 carbon atoms; aminoalkyl COOR5, wherethe alkyl group may be substituted with a carboxyl or histidinesubstituted lower alkyl group having 1-5 carbons and, or is a cycloalkylgroup; R5 is hydrogen or lower alkyl of 1-5 carbons or an acyl-loweralkyl group where the lower alkyl group has 1-5 carbons.
 2. (canceled)3. A compound as defined in claim 1 wherein R₁ and R₃ are hydrogen, R₂is chloro and the amino acid is 4-aminobutyric acid.
 4. A compound asdefined in claim 1 wherein R₁ and R₃ are chloro, R₂ is hydrogen and theamino acid is 3-aminobutyric acid.
 5. A compound as defined in claim 1wherein R₁ and R₃ are hydrogen, R₂ is chloro and the amino acid isglycine.
 6. A compound as defined in claim 1 wherein R₁ and R₃ arechloro, R₂ is hydrogen and the amino acid is1-aminocyclohexanecarboxylic acid.
 7. A compound as defined in claim 1wherein R₁ and R₃ are hydrogen, R₂ is chloro and the amino acid iscystine.
 8. A compound as defined in claim 1 wherein R₁ and R₃ arechloro, R₂ is hydrogen and the amino acid is ε-aminocaproic acid.
 9. Acompound as defined in claim 1 wherein R₁ and R₃ are hydrogen, R₃ ischloro and the amino acid is histidine.
 10. A pharmaceutical compositioncomprising a pharmaceutical carrier and a compound as defined inclaim
 1. 11. A pharmaceutical composition as defined in claim 10 whereinthe compound is derived from a compound of formula (I) and the aminoacid is selected from the group consisting of valine, leucine,isoleucine, asparagine, methionine, phenylalanine, proline, tryptophan,glutamic acid, cysteine, glutamine, arginine, histidine, lysine,aspartic acid, glycione, serine, threonine, tyrosine, ε-aminocaproicacid, 1-aminocyclohexanecarboxylic acid, cystine and arginine.
 12. Apharmaceutical composition as defined in claim 10 wherein the compoundis a compound of formula (I) where R₁ and R3 are hydrogen, R₂ is chloroand the amino acid is 4-aminobutyric acid.
 13. A pharmaceuticalcomposition as defined in claim 10 wherein the compound is a compound offormula 1 wherein R₁ and R3 are chloro, R₂ is hydrogen and the aminoacid is 3-aminobutyric acid.
 14. A pharmaceutical composition as definedin claim 10 wherein the compound is a compound of formula (I) wherein R₁and R3 are chloro, R₂ is hydrogen and the amino acid is glycine.
 15. Apharmaceutical composition as defined in claim 10 wherein the compoundis a compound of formula (I) wherein R1 and R₃ are chloro, R₂ ishydrogen and the amino acid is 1-aminocyclohexanecarboxylic acid.
 16. Apharmaceutical composition as defined in claim 10 wherein the compoundis a compound of formula (I) wherein R₁ and R₃ are hydrogen, R₂ ischloro and the amino acid is cystine.
 17. A pharmaceutical compositionas defined in claim 10 wherein the compound is a compound of formula (I)wherein R₁ and R₃ are chloro, R₂ is hydrogen and the amino acid isε-aminocaproic acid.
 18. A method of preventing the formation ofadvanced glycation end products or breaking advanced glycation endproducts which comprises administering an amount of a compound offormula (I), to a patient who may form or has formed advanced glycationend products, which is effective to prevent or break said glycation endproducts.
 19. A method of treating a condition selected from the groupconsisting of chronic inflammation, neuropathy, atherosclerosis,retinopathy, Alzheimer's disease, erectile dysfunction and diabeteswhich comprises administering to a patient having a condition selectedfrom the group consisting of chronic inflammation, neuropathy,atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction,pre-diabetes and diabetes, an amount of a compound selected from formula(I) which is effective to treat said condition.
 20. A cosmeticcomposition comprising a cosmetic carrier and a compound as defined inclaim
 1. 21-29. (canceled)